Here we report the identification of a natural cancer-associated mutation of the CRAF gene in both the biopsy of a nodular metastasis from melanoma and its derived cell line, and provide evidence that the identified CRAF R391W mutation causes continuous homodimerization of CRAF, induces high activity of the MAPK pathway and exhibits the characteristics of a bona fide melanoma oncogene. The gene discussed is RAF1; the disease is melanoma.